Project Summary While Zika virus (ZIKV) is well known for its transmission through the Aedes mosquitoes, recent evidence highlights sexual contact with an infected partner as another important route of transmission. There have been multiple confirmed and suspected cases of sexual transmission in humans, all of which involve transmission from infected men to their female partners through vaginal intercourse (1-7). ZIKV has been detected in semen of infected men (4, 6, 8). Collectively, these studies indicate that sexual transmission from infected male to uninfected female occurs in humans. An important clinical concern is whether ZIKV can be transmitted sexually in pregnant women, and what the consequence of such infections may be on the outcome of pregnancy. The CDC urges men with ZIKV disease to wait at least 6 months after symptom onset to attempt conception (5). However, the consequences of sexual transmission of ZIKV during pregnancy are unknown. Three recent studies using the mouse model of ZIKV have revealed that type I interferon (IFN) receptor (IFNAR) is critical in host resistance against ZIKV (9-11), and that persistent replication of the virus within the testes of infected IFNAR-deficient male mice (9). Subcutaneous ZIKV infection of Ifnar-/- dams mated with WT sires results in intrauterine growth restriction (IUGR) (12). However, virtually nothing is known about either the pathogenesis of sexual Zika virus transmission, or the defense mechanisms that prevent sexual transmission of ZIKV in pregnant women or the fetus. To this end, we developed the first vaginal ZIKV transmission model in mice. Remarkably, vaginal infection of pregnant mice results in IUGR and infection within the cerebellum and cortex of the fetal brain. Moreover, by using mice that lack various innate sensor and signaling pathways, we unveiled the role of each pathway in controlling ZIKV replication and spread from the vaginal mucosa to the fetus. Using this unique approach, we will find urgently needed answers to the following key questions - 1) which innate signaling pathways block ZIKV in the virgin vs. pregnant female mice; and 2) what innate antiviral pathways are important to restrict ZIKV infection within the fetus?